U.S. patent application number 17/074901 was filed with the patent office on 2021-04-01 for use of pridopidine for the treatment of anxiety and depression.
This patent application is currently assigned to PRILENIA NEUROTHERAPEUTICS LTD.. The applicant listed for this patent is PRILENIA NEUROTHERAPEUTICS LTD.. Invention is credited to Michael HAYDEN, Mahmoud Abdulhossein POULADI.
Application Number | 20210093622 17/074901 |
Document ID | / |
Family ID | 1000005289408 |
Filed Date | 2021-04-01 |
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United States Patent
Application |
20210093622 |
Kind Code |
A1 |
HAYDEN; Michael ; et
al. |
April 1, 2021 |
USE OF PRIDOPIDINE FOR THE TREATMENT OF ANXIETY AND DEPRESSION
Abstract
The invention provides a method of reducing anxiety and/or
depression in a subject comprising periodically administering to
the subject a pharmaceutical composition comprising an amount of
pridopidine effective to reduce anxiety and/or depression in a
subject.
Inventors: |
HAYDEN; Michael; (Herzliya,
IL) ; POULADI; Mahmoud Abdulhossein; (Singapore,
SG) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PRILENIA NEUROTHERAPEUTICS LTD. |
Herzliya |
|
IL |
|
|
Assignee: |
PRILENIA NEUROTHERAPEUTICS
LTD.
Herzliya
IL
|
Family ID: |
1000005289408 |
Appl. No.: |
17/074901 |
Filed: |
October 20, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16332366 |
Mar 12, 2019 |
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PCT/US2017/051814 |
Sep 15, 2017 |
|
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17074901 |
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62532728 |
Jul 14, 2017 |
|
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62395259 |
Sep 15, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/24 20180101;
A61K 9/48 20130101; A61K 9/0053 20130101; A61P 25/22 20180101; A61K
31/4453 20130101 |
International
Class: |
A61K 31/4453 20060101
A61K031/4453; A61K 9/00 20060101 A61K009/00; A61P 25/24 20060101
A61P025/24; A61K 9/48 20060101 A61K009/48; A61P 25/22 20060101
A61P025/22 |
Claims
1. A method of reducing anxiety, depression or combination thereof
in a subject in need thereof comprising administering to the
subject a pharmaceutical composition comprising an amount of
pridopidine effective to reduce anxiety, depression or combination
thereof in the subject; wherein the anxiety or depression is
reduced by S1R modulation.
2. The method of claim 1, wherein anxiety is measured by the
State-Trait Anxiety Inventory (STAI), the Fear Survey Schedule,
Beck Anxiety Inventory (BAI), Brief Fear of Negative Evaluation
Scale--BFNE, Clinician Administered PTSD Scale (CAPS), Daily
Assessment of Symptoms--Anxiety, Generalized Anxiety Disorder 7
(GAD-7), Hamilton Anxiety Scale (HAM-A), Hospital Anxiety and
Depression Scale (HADS-A), Leibowitz Social Anxiety Scale (LSAS),
Overall Anxiety Severity and Impairment Scale (OASIS), Panic and
Agoraphobia Scale (PAS), Panic Disorder Severity Scale (PDSS), PTSD
Symptom Scale--Self-Report Version, Social Phobia Inventory (SPIN),
Trauma Screening Questionnaire, Yale-Brown Obsessive Compulsive
Scale (Y-BOCS), PBA-S, marble burying, ultrasonic vocalizations or
the Zung Self-Rating Anxiety Scale.
3. The method of claim 2, wherein anxiety is reduced by at least
one increment.
4. The method of claim 1, wherein depression is measured by
Hamilton Rating Scale for Depression (HAM-D), Beck Depression
Inventory (BDI), Beck Hopelessness Scale, Centre for
Epidemiological Studies-Depression Scale (CES-D), Patient Health
Questionnaire, Center for Epidemiological Studies Depression Scale
for Children (CES-DC), Clinically Useful Depression Outcome Scale,
Diagnostic Inventory for Depression, Edinburgh Postnatal Depression
Scale (EPDS), Inventory of Depressive Symptomatology, Geriatric
Depression Scale (GDS), Hospital Anxiety and Depression Scale,
Kutcher Adolescent Depression Scale (KADS), Major Depression
Inventory (MDI), Montgomery-Asberg Depression Rating Scale (MADRS),
Mood and Feelings Questionnaire (MFQ), Zung Self-Rating Depression
Scale, forced swim test, or Cornell Scale for Depression in
Dementia (CSDD).
5. The method of claim 4, wherein depression is reduced by at least
one increment.
6. The method of claim 1, wherein the subject is afflicted with an
anxiety disorder.
7. The method of claim 6, wherein the anxiety disorder is
generalized anxiety disorder (GAD), panic disorder, a phobic
disorder, social phobia, agoraphobia, or trauma- and
stressor-related disorders.
8. The method of claim 7, wherein the trauma- and stressor-related
disorder is acute stress disorder (ASD), or posttraumatic stress
disorder (PTSD).
9. The method of claim 1, wherein the subject is afflicted with a
depressive disorder.
10. The method of claim 9, wherein the depressive disorder is major
depressive disorder, persistent depressive disorder, premenstrual
dysphoric disorder, other depressive disorder, depressive disorder
due to another medical condition, substance/medication-induced
depressive disorder, perinatal depression, peripartum-onset
depression, seasonal affective disorder, or psychotic
depression.
11. The method of claim 1, wherein the subject is afflicted with a
neurodegenerative disease.
12. The method of claim 1, wherein the subject is afflicted with
Huntington disease.
13. The method of claim 12, wherein the subject is afflicted with
early stage Huntington disease.
14. The method of claim 12, wherein the subject is afflicted with
Stage 1 or Stage 2 Huntington disease.
15. The method of claim 14 the subject has greater than or equal to
36 CAG repeats in the huntingtin gene.
16. The method of claim 15, wherein the subject has greater than 44
CAG repeats in the huntingtin gene.
17. The method of claim 14, wherein the subject is
presymptomatic.
18. The method of claim 14, wherein the subject is symptomatic.
19. The method of claim 14, wherein the method comprises reducing
anxiety in a subject afflicted with early stage Huntington
disease.
20. The method of claim 14, wherein the method comprises reducing
depression in a subject afflicted with any one of the following:
Stage 1 Huntington disease, Stage 2 Huntington disease, Stage 3
Huntington disease, Stage 4 Huntington disease and Stage 5
Huntington disease.
21. The method of claim 1, wherein the subject has been diagnosed
with anxiety only.
22. The method of claim 21, wherein the subject is experiencing at
least one symptom of anxiety, wherein the at least one symptom
comprises restlessness, heart palpitations, hyperventilation, heavy
sweating, muscle twitching, weakness, lethargy, insomnia, nausea,
repetitive behavior, or any combination thereof.
23. The method of claim 1, wherein the subject has been diagnosed
with depression only.
24. The method of claim 23, wherein the subject is experiencing at
least one symptom of depression, and wherein the at least one
symptom of depression comprises depressed mood, anhedonia, low
energy levels, feelings of guilt, psychomotor retardation,
agitation, suicidal ideations poor concentration and
indecisiveness, or any combination thereof.
25. The method of claim 1, wherein between 22.5-315 mg pridopidine
is administered to the subject per day.
26. The method of claim 1, wherein the unit dose is administered
once daily, or more than once daily.
27. The method of claim 1, wherein the unit dose is administered
twice per day.
28. The method of claim 1, wherein the pharmaceutical composition
is administered for more than 26 weeks, at least 52 weeks, or at
least 78 weeks.
29. The method of claim 1, wherein the periodic administration is
oral.
30. The method of claim 1, wherein the subject is a human
subject.
31. The method of claim 1, wherein the pridopidine is in the form
of pridopidine hydrochloride.
32. The method of claim 1, wherein the anxiety and/or depression is
reduced for at least 12 months.
Description
CROSS REFERENCE
[0001] This application is a Continuation-in-Part application from
U.S. application Ser. No. 16/332,366 filed Mar. 12, 2019, which is
a National Phase application from International Application No.
PCT/US2017/051814 filed 15 Sep. 2017 which claims the benefit of
U.S. Provisional Application No. 62/532,728, filed Jul. 14, 2017
and U.S. Provisional Application No. 62/395,259, filed Sep. 15,
2016, the contents of each of which are hereby incorporated by
reference in their entirety.
[0002] Throughout this application various publications are
referenced, most typically by the last name of the first author and
the year of publication. Full citations for these publications are
set forth in a section entitled References immediately preceding
the claims. The disclosures of all referenced publications in their
entireties are hereby incorporated by reference into this
application in order to more fully describe the state of the art to
which the invention relates.
BACKGROUND
[0003] Pridopidine
[0004] Pridopidine
(4-[3-(methylsulfonyl)phenyl]-1-propyl-piperidine) (formerly known
as ACR16) is a drug under development for treatment of Huntington
disease. The chemical name of pridopidine is
4-(3-(Methylsulfonyl)phenyl)-1-propylpiperidine and its Chemical
Registry Number is CAS 346688-38-8 (CSID:7971505, 2016). The
Chemical Registry number of pridopidine hydrochloride is
882737-42-0 (CSID:25948790 2016).
[0005] Pridopidine is a highly selective Sigma-1 receptor (S1R)
ligand which has .about.30-fold higher affinity towards the S1R vs
D3Rs, and .about.500-fold higher affinity vs D2Rs. Selective
binding of pridopidine for the S1R was confirmed using positron
emission tomography (PET) imaging in rats (Sahlholm, 2015), and in
humans at dose of 45 mg BID (Grachev, 2020). Pridopidine exerts
neuroprotective properties which are mediated by its activation of
the S1R, as its silencing by genetic or pharmacological methods
abolishes the protective effects (Geva 2016, Eddings 2019, Ryskamp
2018, Ionescu 2019).
[0006] The S1R is a highly conserved transmembrane protein located
in the endoplasmic reticulum (ER) and specifically enriched in the
subregions contacting mitochondria (Mitochondria-Associated
Membranes, MAM). The S1R is highly enriched in the CNS and
specifically within the Basal Ganglia, cortex, and brainstem. The
S1R is implicated in cellular differentiation, neuroplasticity,
neuroprotection and cognitive function in the brain. Activation of
the S1R by pridopidine results in the induction of several cellular
processes that are altered in neurodegenerative diseases and
neuronal disorders, and their activation contributes to
neuroprotection.
[0007] Recent transcriptomic analysis of rat striatum showed that
pridopidine treatment activates expression of the BDNF,
glucocorticoid receptor (GR), and the serine-threonine kinase
protein kinase B (Akt)/phosphoinositide 3-kinase (PI3K) pathways,
known to promote neuronal plasticity and survival (Geva 2016).
Pridopidine enhances the secretion of the neuroprotective
brain-derived neurotrophic factor (BDNF) in a neuroblastoma cell
line, in a S1R-dependent manner (Geva 2016). Pridopidine rescues
the decrease in BDNF levels in neurodegenerative mouse models of HD
and Parkinson's Disease, and activates downstream intracellular
signaling pathways (Squitieri 2015, Francardo 2019). Thus,
modulation of the BDNF pathway is a major component of
pridopidine's S1R-mediated neuroprotective effects. BDNF is an
important regulator of synaptic plasticity, and both neurotrophins
and abnormal plasticity processes are associated with
depression.
[0008] Dendritic spines facilitate synaptic transmission and
plasticity, integrating physiological and morphological changes. A
decrease in dendritic spine density in the hippocampus is
associated with anxiety and depressive states (Qiao 2015).
Pridopidine treatment increased spine density in medium spiny
neurons from HD YAC128 mice in a S1R-mediated manner (Ryskamp
2017).
[0009] One type of plasticity regulated by BDNF is homeostatic
synaptic plasticity (HSP), the processes that maintain the
stability of neuronal networks and underlie learning and cognitive
capabilities (Smith-Dijak et al., 2019). Homeostatic plasticity is
disrupted in major depressive disorder (MDD), and its activation
has been suggested as a possible therapeutic avenue (Workman et
al., 2017). Pridopidine treatment rescued the impaired HSP observed
in cultured cortical neurons from HD YAC128 model mice (Smith-Dijak
et al., 2019).
[0010] The default-mode network (DMN) is a set of brain regions
which are active when the brain is not engaged in a cognitive task,
and which are deactivated upon cognitive engagement with a task.
Alterations in DMN connectivity and function are associated with
MDD and anxiety, and are normalized upon treatment with
anti-depressants (Yan 2019; Couthino 2016; Posner 2013).
Pridopidine treatment has been shown to increase DMN activity in
healthy volunteers and in HD patients.
SUMMARY OF THE INVENTION
[0011] In one aspect, provided herein is a method of reducing
anxiety and/or depression in a subject in need thereof comprising
periodically administering to the subject a pharmaceutical
composition comprising an amount of pridopidine effective to reduce
anxiety and/or depression in a subject.
[0012] In some embodiments, the method reduces anxiety in the
subject. In some embodiments, the method reduces depression in the
subject.
[0013] Further provided is pridopidine for use in reducing anxiety
and/or depression in a subject. Also provided is pridopidine for
the manufacture of a medicament for use in reducing anxiety and/or
depression in a subject.
[0014] Further provided is a pharmaceutical composition comprising
an effective amount of pridopidine for reducing anxiety and/or
depression in a subject. Also provided is a pharmaceutical
composition comprising pridopidine for use in reducing anxiety
and/or depression a subject.
[0015] The present invention further provides a package comprising:
[0016] a) a pharmaceutical composition comprising an amount of
pridopidine; and [0017] b) instructions for use of the
pharmaceutical composition to reduce anxiety and/or depression in a
subject.
[0018] In another aspect the present invention provides, a
therapeutic package for dispensing to, or for use in dispensing to,
a subject, which comprises: [0019] a) one or more unit doses, each
such unit dose comprising an amount of pridopidine thereof, wherein
the amount of said pridopidine in said unit dose is effective, upon
administration to said subject, to reduce anxiety and/or depression
in the subject, and [0020] b) a finished pharmaceutical container
therefor, said container containing said unit dose or unit doses,
said container further containing or comprising labeling directing
the use of said package in the reduction of anxiety and/or
depression in said subject.
BRIEF DESCRIPTION OF THE FIGURES
[0021] FIGS. 1-4--The effect of pridopidine on anxiety and
depression-like behaviors in the YAC128 mouse model of HD.
[0022] FIG. 1. Pridopidine administration. The timeline shows the
early and late administration times of pridopidine relative to
molecular, neuroanatomical and behavioural phenotypes in the rodent
model of Huntington Disease, the YAC128 mice. The molecular and
neuroanatomical phenotypes are listed along the upper horizontal
line. The behavioural phenotypes are listed along the lower
horizontal line. Age of the mice, in months, is presented between
the upper and lower lines.
[0023] FIGS. 2A and 2B. Early and late treatment study designs.
(2A) Late pridopidine treatment study design. WT mice were
administered vehicle (ddH2O) only, whereas YAC128 HD mice were
administered either vehicle (ddH2O) or an escalating dose of
pridopidine (10 mg/kg in week 1, 20 mg/kg in week 2, and 30 mg/kg
in weeks 3-8). Treatment started at 8 months of age (manifest) and
continued for 2 months. (2B) Early pridopidine treatment study
design. WT mice were administered vehicle (ddH2O) only, whereas
YAC128 HD mice were administered either vehicle (ddH2O) or
pridopidine (30 mg/kg). Treatment started at 1.5 months of age
(pre-manifest) and continued for 10.5 months. For both (2A) and
(2B) behavioural tests were carried out as indicated: OF=open
field, EPM=elevated plus maze, FST=forced swim test.
[0024] FIG. 3: Pridopidine improves depressive-like behavior in
late-stage (manifest) pridopidine treated YAC128 mice in the forced
swim test; YAC128 HD mice displayed increased depressive-like
behavior compared to WT mice. Pridopidine (30 mg/kg) significantly
improves depressive-like phenotype of YAC128 HD mice in the forced
swim test by reducing immobility time in the water (FIG. 3). Values
shown as mean.+-.SEM; n=4 (M) WT-vehicle, n=8 (M) YAC128-vehicle,
n=9 (M), n=8 YAC128-pridopidine; *p<0.05 by one-way ANOVA with
Fisher's LSD post hoc analysis.
[0025] FIGS. 4A-4C. Pridopidine treatment improves Affective
functions in early-stage (pre-manifest) treated mice. FIG. 4A (Open
field), 4B (Elevated plus maze) and 4C (Forced swim test). YAC128
HD mice displayed increased anxiety-like behavior in the open field
at 6 months (A) and elevated plus maze at 8 months of age (B)
compared to WT mice. Early pridopidine treatment improves anxiety-
and depressive-like phenotypes in YAC128 HD mice. Pridopidine 30
mg/kg increased the time spent in the center of the arena (4A) and
in the open arms (4B), indicating decreased anxiety-like behavior.
Vehicle-treated YAC128 HD mice showed a trend towards an increased
time spent immobile compared with vehicle-treated WT mice in the
forced swim test, while pridopidine treatment reduced the time
spent immobile, indicating that pridopidine reduces depressive-like
behavior (4C). Veh=Vehicle; Pri=Pridopidine; M=males. Values shown
as mean.+-.SEM; n=4 (M) WT-vehicle, n=8 (M) YAC128-vehicle, n=9
(M), n=8 YAC128-pridopidine; *p<0.05, **p<0.01, ***p<0.001
by one-way ANOVA with Fisher's LSD post hoc analysis; ##p<0.01
by paired Students t-test.
[0026] FIGS. 5A-5B present the study design of rat Forced Swim Test
(FIG. 5A) and anti-depressive effect of pridopidine (FIG. 5B) in
the Rat Forced Swim. 5A: rats were placed in the swimming tank for
a swimming session on day one, and then treated daily with
pridopidine, either 3 or 15 mg/kg by oral gavage (per os, po) for 7
days. On day 8, rats were again placed in a water tank, and time
spent immobile measured. FIG. 5B: Pridopidine treatment reduces the
percent of time spent immobile in the tank, at both 3 mg/kg
(non-significant) and 15 mg/kg (significant) indicating an
anti-depressive effect.
[0027] FIG. 6 Anxiolytic effect of pridopidine in the marble
burying test in mice (NS). Object burying is indicative of anxiety
in rodents. Inhibition of object-burying in rodents is an accepted
model for measuring anxiolytic effects of a drug (Broekkamp et al,
1986; Treit, 1985; Treit et al, 1981). Marble burying activity was
assessed in male NMRI mice, which were then treated with
pridopidine 1, 3, 10 or 30 mg/kg for 30 minutes before being tested
again for marble burying. Pridopidine shows a dose-dependent
inhibition of marble burying, indicating an anxiolytic effect.
Marble burying also represents an animal model for
Obsessive-compulsive disorder.
[0028] Data shown are mean percent of inhibition.+-.SEM, *p<0.05
ANOVA.
[0029] FIG. 7 Anxiolytic effects of pridopidine in the rat
ultrasonic vocalization (USV) test using pridopidine. USVs are
considered a measure of anxiety in rodents. Young adult rats were
treated with 30 mg/kg pridopidine by oral gavage (per os). Rats
were first primed by a series of up to 10 electric shocks delivered
to the feet by a grid in the floor, which was terminated in case of
3 consecutive and consistent USVs. The next day, each rat received
5 initial shocks, and USVs were recorded in the following 3-minute
period. Animals were tested 30 and 120 minutes after pridopidine
administration. Pridopidine significantly inhibited USV duration in
rats. Data shown are mean USV time (sec).+-.SEM, N=4 rats per
treatment group, *p<0.05.
[0030] FIG. 8 presents an improvement in the Problem Behaviors
Assessment-Short (PBA-S) scale in HD patients treated with
pridopidine in the Pride HD clinical trial, compared to placebo.
PBA-S includes behavioral assessments of depressed mood, anxiety,
apathy and irritability. Graph presents change from baseline, at
week 52 in the placebo and 45 mg bid pridopidine treated
groups.
[0031] FIG. 9 presents an improvement in the lack of initiative
measure of the PBA-S in HD patients treated with pridopidine in the
Pride-HD clinical trial, at week 52. The lack of initiative
subscale of the PBA-S is a measure of apathy in HD patients. Apathy
is a symptom common to HD and depression. Graph presents change
from baseline, at week 52 in the placebo and 45 mg bid pridopidine
treated groups.
[0032] FIG. 10 Study Schema of Phase 3, Randomized, Double-Blind
Placebo-Controlled, clinical trial described in Example 3. (twice
daily (bid); baseline (BL); end of study (EoS); early termination
(ET); once daily (qd); visit (V); virtual visit (VV); week (W). *
For each participant, the last treatment visit will be the EoS at
either Week 65 or Week 78, if the participant completes all study
visits, or Early Termination (ET) visit if the participant
withdraws from the study before Week 65.).
[0033] FIG. 11 Study Schema--Open-Label Extension. (ET--early
termination; V--visit; W--week).
DETAILED DESCRIPTION OF THE INVENTION
[0034] This invention provides a method of reducing anxiety and/or
depression in a subject in need thereof comprising periodically
administering to the subject a pharmaceutical composition
comprising an amount of pridopidine effective to reduce anxiety
and/or depression in a subject in the subject.
[0035] In one embodiment, the method reduces anxiety in the
subject. In an embodiment, anxiety is measured by the State-Trait
Anxiety Inventory (STAI), the problem Behaviors Assessment-Short
(PBA-S) scale, the Fear Survey Schedule, Beck Anxiety Inventory
(BAI), Brief Fear of Negative Evaluation Scale--BFNE, Clinician
Administered PTSD Scale (CAPS), Daily Assessment of
Symptoms--Anxiety, Generalized Anxiety Disorder 7 (GAD-7), Hamilton
Anxiety Scale (HAM-A), Hospital Anxiety and Depression Scale
(HADS-A), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety
Severity and Impairment Scale (OASIS), Panic and Agoraphobia Scale
(PAS), Panic Disorder Severity Scale (PDSS), PTSD Symptom
Scale--Self-Report Version, Social Phobia Inventory (SPIN), Trauma
Screening Questionnaire, Yale-Brown Obsessive Compulsive Scale
(Y-BOCS), or the Zung Self-Rating Anxiety Scale.
[0036] In one embodiment, anxiety is reduced by at least one
increment.
[0037] In another embodiment, the method reduces depression in the
subject. In an embodiment, depression is measured by Hamilton
Rating Scale for Depression (HAM-D), Beck Depression Inventory
(BDI), Beck Hopelessness Scale, Centre for Epidemiological
Studies-Depression Scale (CES-D), Patient Health Questionnaire,
Center for Epidemiological Studies Depression Scale for Children
(CES-DC), Clinically Useful Depression Outcome Scale, Diagnostic
Inventory for Depression, Edinburgh Postnatal Depression Scale
(EPDS), Inventory of Depressive Symptomatology, Geriatric
Depression Scale (GDS), Hospital Anxiety and Depression Scale,
Kutcher Adolescent Depression Scale (KADS), Major Depression
Inventory (MDI), Montgomery-.ANG.sberg Depression Rating Scale
(MADRS), Mood and Feelings Questionnaire (MFQ), Zung Self-Rating
Depression Scale, or Cornell Scale for Depression in Dementia
(CSDD).
[0038] In one embodiment, depression is reduced by at least one
increment.
[0039] In another embodiment, the subject is afflicted with an
anxiety disorder. In an embodiment, the anxiety disorder is
generalized anxiety disorder (GAD), panic disorder, a phobic
disorder, social phobia, agoraphobia, or trauma- and
stressor-related disorders. In a further embodiment, the trauma-
and stressor-related disorder is acute stress disorder (ASD), or
posttraumatic stress disorder (PTSD).
[0040] In another embodiment, the subject is afflicted with a
depressive disorder. In an embodiment, the depressive disorder is
major depressive disorder, persistent depressive disorder,
premenstrual dysphoric disorder, other depressive disorder,
depressive disorder due to another medical condition,
substance/medication-induced depressive disorder, perinatal
depression, peripartum-onset depression, seasonal affective
disorder, or psychotic depression.
[0041] In one embodiment, the subject is afflicted with a
neurodegenerative disease. In another embodiment, the subject is
afflicted with Huntington disease. In a further embodiment, the
subject is afflicted with Stage 1 or Stage 2 Huntington disease. In
one embodiment, the subject is afflicted with Stage 1 Huntington
disease. In another embodiment, the subject is afflicted with Stage
2 Huntington disease.
[0042] In another embodiment, the subject is afflicted with early
stage Huntington disease.
[0043] In an embodiment, the subject has greater than or equal to
36 CAG repeats in the huntingtin gene. In another embodiment,
subject has greater than 44 CAG repeats in the huntingtin gene.
[0044] In some embodiments, the subject is presymptomatic. In other
embodiments, the subject is symptomatic.
[0045] In one embodiment, the method comprises reducing anxiety in
a subject afflicted with early stage Huntington disease.
[0046] In another embodiment, the method comprises reducing
depression in a subject afflicted with any one of the following:
Stage 1 Huntington disease, Stage 2 Huntington disease, Stage 3
Huntington disease, Stage 4 Huntington disease and Stage 5
Huntington disease.
[0047] In an embodiment, the subject is a human subject.
[0048] In an embodiment, the periodic administration is oral.
[0049] In an embodiment, between 22.5-315 mg pridopidine is
administered to the subject per day. In another embodiment, 22.5
mg, 45 mg, 67.5, mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 135 mg, 150
mg, 180 mg, 200 mg, 225 mg, 250 mg, or 315 mg pridopidine is
administered to the subject per day.
[0050] In an embodiment, the amount of pridopidine is administered
by a unit dose of 22.5 mg, 45 mg, 67.5, mg, 90 mg, 100 mg, 112.5
mg, 125 mg, 135 mg, 150 mg, 180 mg, 200 mg, 225 mg, 250 mg, or 315
mg pridopidine.
[0051] In an embodiment, the unit dose is administered once
daily.
[0052] In another embodiment, the pharmaceutical composition is
administered for more than 26 weeks, at least 52 weeks, at least 54
weeks, at least 78 weeks, at least 104 weeks or more.
[0053] In an embodiment, the unit dose is administered more than
once daily. In another embodiment, the unit dose is administered
twice per day.
[0054] In an embodiment, the pridopidine is in the form of
pridopidine hydrochloride.
[0055] In one embodiment, the anxiety and/or depression is reduced
for at least 12 months.
[0056] The invention also provides pridopidine for use in reducing
anxiety and/or depression in a subject.
[0057] In an embodiment, the subject has been diagnosed with
anxiety only. In another embodiment, the subject is experiencing at
least one symptom of anxiety, wherein the at least one symptom
comprises restlessness, heart palpitations, hyperventilation, heavy
sweating, muscle twitching, weakness, lethargy, insomnia, nausea,
repetitive behavior, or any combination thereof.
[0058] In an embodiment, the subject has been diagnosed with
depression only. In another embodiment the subject is experiencing
at least one symptom of depression, and wherein the at least one
symptom of depression comprises depressed mood, anhedonia, low
energy levels, feelings of guilt, psychomotor retardation,
agitation, suicidal ideations poor concentration and
indecisiveness, or any combination thereof.
[0059] In an embodiment, a titration dose of an amount different
from the intended dose is administered for a period of time at the
start of the periodic administration. In some embodiments, the
titration dose is half the amount of the intended dose. In another
embodiment, the titration dose is administered in one
administration per day and the intended dose is administered in two
administrations per day. In one embodiment, the titration dose is
administered for 7-21 or 7-14 days prior to the administration of
the intended dose. In another embodiment, the titration dose is
administered for 7 days, 14 days, or 21 days prior to the
administration of the intended dose. The titration dose is
preferably administered for fourteen days prior to the
administration of the intended dose.
[0060] The invention also provides pridopidine for the manufacture
of a medicament for use in reducing anxiety and/or depression in a
subject.
[0061] The invention also provides a pharmaceutical composition
comprising an effective amount of pridopidine for reducing anxiety
and/or depression in a subject.
[0062] The invention also provides a pharmaceutical composition
comprising pridopidine for use in reducing anxiety and/or
depression a subject.
[0063] The invention also provides a package comprising: [0064] a)
a pharmaceutical composition comprising an amount of pridopidine;
and [0065] b) instructions for use of the pharmaceutical
composition to reduce anxiety and/or depression in a subject.
[0066] The invention also provides a therapeutic package for
dispensing to, or for use in dispensing to, a subject, which
comprises: [0067] a) one or more unit doses, each such unit dose
comprising an amount of pridopidine thereof, wherein the amount of
said pridopidine in said unit dose is effective, upon
administration to said subject, to reduce anxiety and/or depression
in the subject, and [0068] b) a finished pharmaceutical container
therefor, said container containing said unit dose or unit doses,
said container further containing or comprising labeling directing
the use of said package in the reduction of anxiety and/or
depression in said subject.
[0069] The invention further provides a method of modulating gene
expression in a subject afflicted with Huntington disease
comprising administering an amount of pridopidine effective to
modulate gene expression as described in this application.
[0070] The invention further provides a method of predicting
clinical responsiveness to pridopidine therapy in a subject
afflicted with Huntington disease, the method comprising evaluating
expression of a biomarker in the subject, so as to thereby predict
clinical responsiveness to pridopidine, wherein the biomarker is a
gene as described in this application.
[0071] In one embodiment, the method further comprising predicting
positive clinical responsiveness to pridopidine if the biomarker is
up-regulated in the subject.
[0072] In another embodiment, the method further comprising
predicting positive clinical responsiveness to pridopidine if the
biomarker is suppressed in the subject.
[0073] In one embodiment, the subject is identified as a
pridopidine responder if expression of the biomarker is higher than
a reference value. In another embodiment, the subject is identified
as a pridopidine responder if expression level of the biomarker is
lower than a reference value.
[0074] In another embodiment, if the subject is identified as a
pridopidine responder, the subject is thereafter administered a
pharmaceutical composition comprising pridopidine.
[0075] Combinations of the above-described embodiments are also
within the scope of the invention.
[0076] For the foregoing embodiments, each embodiment disclosed
herein is contemplated as being applicable to each of the other
disclosed embodiments. For instance, the elements recited in the
method embodiments can be used in the pharmaceutical composition,
package, and use embodiments described herein and vice versa.
Terms
[0077] As used herein, and unless stated otherwise, each of the
following terms shall have the definition set forth below.
[0078] As used herein, "administering to the subject" means the
giving of, dispensing of, or application of medicines, drugs, or
remedies to a subject to relieve, cure or reduce the symptoms
associated with a disease, disorder or condition, e.g., a
pathological condition. Oral administration is one way of
administering the instant compounds to the subject.
[0079] As used herein, an "amount" or "dose" of pridopidine as
measured in milligrams refers to the milligrams of pridopidine
(4-[3-(methylsulfonyl)phenyl]-1-propyl-piperidine) present in a
preparation, regardless of the form of the preparation. For
example, a unit dose containing "90 mg pridopidine" means the
amount of pridopidine base in a preparation is 90 mg, regardless of
the form of the preparation. Thus, when in the form of a salt, e.g.
pridopidine hydrochloride salt, the weight of the salt form
necessary to provide a dose of 90 mg pridopidine would be greater
than 90 mg due to the presence of the salt.
[0080] As used herein, a "unit dose", "unit doses" and "unit dosage
form(s)" mean a single drug administration entity/entities.
[0081] As used herein, "about" in the context of a numerical value
or range means .+-.10% of the numerical value or range recited or
claimed.
[0082] As used herein, "effective" as in an amount effective to
achieve an end means the quantity of a component that is sufficient
to yield an indicated therapeutic response without undue adverse
side effects (such as toxicity, irritation, or allergic response)
commensurate with a reasonable benefit/risk ratio when used in the
manner of this disclosure. For example, an amount effective to
treat cognitive deficit. The specific effective amount varies with
such factors as the particular condition being treated, the
physical condition of the patient, the type of mammal being
treated, the duration of the treatment, the nature of concurrent
therapy (if any), and the specific formulations employed and the
structure of the compounds or its derivatives.
[0083] As used herein, to "treat" or "treating" encompasses, e.g.,
inducing inhibition, regression, or stasis of a disorder and/or
disease, e.g. depression, or alleviating, lessening, suppressing,
inhibiting, reducing the severity of, eliminating or substantially
eliminating, or ameliorating a symptom of the disease or
disorder.
[0084] As used herein, "inhibition" of disease progression or
disease complication in a subject means preventing, delaying or
reducing the disease progression and/or disease complication in the
subject. This includes, for example, delaying the progression of
one of more symptoms in the subject, including but not limited to
delaying the progression of: cognitive impairment, intellectual
disability, learning disabilities (e.g., having difficulty learning
new skills), developmental delays (e.g., not sitting, walking, or
talking at the same time as other children the same age), social
and behavior problems (e.g., making eye contact, anxiety, trouble
paying attention, hand flapping, acting and speaking without
thinking, and being very active), anxiety and hyperactive behavior,
hypersensitivity to sensory stimuli, altered gastrointestinal
function, autistic symptoms (e.g., shyness, poor eye contact, and
social anxiety in mild cases to hand flapping, hand biting and
preservative speech in the severely affected), attention deficit
and hyperactivity, behavioral disturbances (e.g., irritability,
aggression and self-injurious behaviors), seizures,
obsessive-compulsive behavior and altered gastrointestinal
function.
[0085] In some embodiments, symptoms of anxiety include but are not
limited to restlessness, heart palpitations, hyperventilation,
heavy sweating, muscle twitching, weakness, lethargy, insomnia,
nausea, repetitive behavior, or any combination thereof.
[0086] In some embodiments, symptoms of depression include but are
not limited to depressed mood, anhedonia, low energy levels,
feelings of guilt, psychomotor retardation, agitation, suicidal
ideations poor concentration, indecisiveness, or any combination
thereof.
[0087] A "pharmaceutically acceptable carrier" refers to a carrier
or excipient that is suitable for use with humans and/or animals
without undue adverse side effects (such as toxicity, irritation,
and allergic response) commensurate with a reasonable benefit/risk
ratio. It can be a pharmaceutically acceptable solvent, suspending
agent or vehicle, for delivering the instant compounds to the
subject.
[0088] As used herein, "pridopidine" means pridopidine base or a
pharmaceutically acceptable salt thereof, or combination with
pridopidine analogs or derivatives thereof for example
deuterium-enriched version of pridopidine and salts. Examples of
deuterium-enriched pridopidine and salts and their methods of
preparation may be found in U.S. Application Publication Nos.
2013-0197031, 2016-0166559 and 2016-0095847, the entire content of
each of which is hereby incorporated by reference. In certain
embodiments, pridopidine is a pharmaceutically acceptable salt,
such as the HCl salt or tartrate salt. Preferably, in any
embodiments of the invention as described herein, the pridopidine
is in the form of its hydrochloride salt.
[0089] "Deuterium-enriched" means that the abundance of deuterium
at any relevant site of the compound is more than the abundance of
deuterium naturally occurring at that site in an amount of the
compound. The naturally occurring distribution of deuterium is
about 0.0156%. Thus, in a "deuterium-enriched" compound, the
abundance of deuterium at any of its relevant sites is more than
0.0156% and can range from more than 0.0156% to 100%.
Deuterium-enriched compounds may be obtained by exchanging hydrogen
with deuterium or synthesizing the compound with deuterium-enriched
starting materials.
[0090] A dosage unit can be prepared for oral dosage forms, such as
tablets, capsules, pills, powders, and granules. A dosage unit can
be prepared for intravenous dosage forms.
[0091] Pharmaceutically Acceptable Salts
[0092] The active compounds for use according to the invention may
be provided in any form suitable for the intended administration.
Suitable forms include pharmaceutically (i.e. physiologically)
acceptable salts, and pre- or prodrug forms of the compound of the
invention.
[0093] A "salt thereof" is a salt of the instant compound which has
been modified by making acid or base salts of the compound. The
term "pharmaceutically acceptable salt" in this respect, refers to
the relatively non-toxic, inorganic and organic acid or base
addition salts of compound of the present invention suitable for
pharmaceutical use. Pharmaceutically acceptable salts may be formed
by procedures well known and described in the art. One means of
preparing such a salt is by treating a compound of the present
invention with an inorganic base.
[0094] Examples of pharmaceutically acceptable salts include,
without limitation, the non-toxic inorganic and organic acid
addition salts such as the hydrochloride, the hydrobromide, the
nitrate, the perchlorate, the phosphate, the sulphate, the formate,
the acetate, the aconate, the ascorbate, the benzenesulphonate, the
benzoate, the cinnamate, the citrate, the embonate, the enantate,
the fumarate, the glutamate, the glycolate, the lactate, the
maleate, the malonate, the mandelate, the methanesulphonate, the
naphthalene-2-sulphonate, the phthalate, the salicylate, the
sorbate, the stearate, the succinate, the tartrate, the
toluene-p-sulphonate, and the like. Such salts may be formed by
procedures well known and described in the art.
[0095] Pridopidine Analogs
[0096] In some embodiments the methods of this invention make use
of a pharmaceutical composition comprising pridopidine or
pharmaceutically acceptable salt thereof and at least one analog
thereof and pharmaceutically acceptable salt thereof. In another
embodiment, the analog compounds of pridopidine or salts thereof
are represented by the following structures of compounds 1-7:
##STR00001## ##STR00002##
[0097] In other embodiments this invention provides a
pharmaceutical composition comprising pridopidine or
pharmaceutically acceptable salt thereof and compound 1 or
pharmaceutically acceptable salt thereof. In other embodiments this
invention provides a pharmaceutical composition comprising
pridopidine or pharmaceutically acceptable salt thereof and
compound 2 or pharmaceutically acceptable salt thereof. In other
embodiments this invention provides a pharmaceutical composition
comprising pridopidine or pharmaceutically acceptable salt thereof
and compound 3 or pharmaceutically acceptable salt thereof. In
other embodiments this invention provides a pharmaceutical
composition comprising pridopidine or pharmaceutically acceptable
salt thereof and compound 4 or pharmaceutically acceptable salt
thereof. In other embodiments this invention provides a
pharmaceutical composition comprising pridopidine or
pharmaceutically acceptable salt thereof and compound 5 or
pharmaceutically acceptable salt thereof. In other embodiments this
invention provides a pharmaceutical composition comprising
pridopidine or pharmaceutically acceptable salt thereof and
compound 6 or pharmaceutically acceptable salt thereof. In other
embodiments this invention provides a pharmaceutical composition
comprising pridopidine or pharmaceutically acceptable salt thereof
and compound 7 or pharmaceutically acceptable salt thereof. In
other embodiments this invention provides a pharmaceutical
composition comprising pridopidine or pharmaceutically acceptable
salt thereof and compound 1 and compound 4 or pharmaceutically
acceptable salt thereof. In other embodiments, the concentration of
compounds 1, 2, 3, 4, 5, 6 or 7 or pharmaceutically acceptable salt
thereof within the composition is between 0.001% w/w to 10% w/w. In
other embodiments, the concentration of compounds 1, 2, 3, 4, 5, 6
or 7 or pharmaceutically acceptable salt thereof within the
composition is between 0.001% w/w to 0.05% w/w. In other
embodiments, the concentration of compounds 1, 2, 3, 4, 5, 6 or 7
or pharmaceutically acceptable salt thereof within the composition
is between 0.001% w/w to 0.5% w/w. In other embodiments, the
concentration of compounds 1, 2, 3, 4, 5, 6 or 7 or
pharmaceutically acceptable salt thereof within the composition is
between 0.001% w/w to 0.15% w/w. In other embodiments, the
concentration of compounds 1, 2, 3, 4, 5, 6 or 7 or
pharmaceutically acceptable salt thereof within the composition is
between 0.01% w/w to 0.15% w/w. In other embodiments, the
concentration of compounds 1, 2, 3, 4, 5, 6 or 7 or
pharmaceutically acceptable salt thereof within the composition is
between 0.01% w/w to 0.5% w/w. In other embodiments, the
concentration of compounds 1, 2, 3, 4, 5, 6 or 7 or
pharmaceutically acceptable salt thereof within the composition is
between 0.01% w/w to 1% w/w.
[0098] Pharmaceutical Compositions
[0099] While the compounds for use according to the invention may
be administered in the form of the raw compound, it is preferred to
introduce the active ingredients, optionally in the form of
physiologically acceptable salts, in a pharmaceutical composition
together with one or more adjuvants, excipients, carriers, buffers,
diluents, and/or other customary pharmaceutical auxiliaries.
[0100] In an embodiment, the invention provides pharmaceutical
compositions comprising the active compounds or pharmaceutically
acceptable salts or derivatives thereof, together with one or more
pharmaceutically acceptable carriers therefore, and, optionally,
other therapeutic and/or prophylactic ingredients know and used in
the art. The carrier(s) must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not
harmful to the recipient thereof.
[0101] The pharmaceutical composition of the invention may be
administered by any convenient route, which suits the desired
therapy. Preferred routes of administration include oral
administration, in particular in tablet, in capsule, in drage, in
powder, or in liquid form, and parenteral administration, in
particular cutaneous, subcutaneous, intramuscular, or intravenous
injection. The pharmaceutical composition of the invention can be
manufactured by the skilled person by use of standard methods and
conventional techniques appropriate to the desired formulation.
When desired, compositions adapted to give sustained release of the
active ingredient may be employed.
[0102] Further details on techniques for formulation and
administration may be found in the latest edition of Remington's
Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
[0103] It is understood that where a parameter range is provided,
all integers within that range, and tenths thereof, are also
provided by the invention. For example, "22 mg-300.0 mg" includes
22.0, 22.1 mg, 22.2 mg, 22.3 mg, 22.4 mg, etc. up to 300.0 mg.
[0104] Anxiety Rating Scales
[0105] The anxiety rating scales listed herein are known to those
skilled in the art. For example, the Beck Anxiety Inventory (BAI)
is a measure of anxiety that has 21 items which are summed to
obtain a total score from 0-63, in which a score of 0-9 is
generally considered to mean normal or no anxiety; a score of 10-18
is generally considered to mean mild to moderate anxiety; a score
of 19-29 is generally considered to mean moderate to severe
anxiety; and a score of 30-63 is generally considered to mean
severe anxiety (Julian 2011). Another anxiety rating scale is the
Hospital Anxiety and Depression Scale-Anxiety (HADS-A) which has 7
items (Julian 2011). This scale evaluates common dimensions of
anxiety and can be used to detect and quantify magnitude of
symptoms of anxiety (Julian 2011). The total score for HADS-A can
range from 0 to 21 and the following guidelines are recommended for
the interpretation of scores: 0-7 for normal or no anxiety, 8-10
for mild anxiety, 11-14 for moderate anxiety, and 12-21 for severe
anxiety (Julian 2011). Other anxiety rating scales are described in
Spitzer 2006, Hamilton 1959, Leary 1983, Heimberg 1999, Norman
2006, Zigmond 1983, and Connor 2000.
[0106] As used here, "reducing anxiety by at least one increment"
means that the patient's anxiety as measured by at least one of the
specific anxiety rating scales is lessened. For example, the STAI
is an anxiety rating scale which has two subtest, a State Anxiety
Scale (S-Anxiety) and a Trait Anxiety Scale (T-Anxiety) (Julian
2011). The range of scores for each subtest is 20-80 with a higher
score indicating greater anxiety (Julian 2011). Therefore, a
subject obtains a score of between 40 and 160 after completing the
STAI. The subject's anxiety is reduced by at least one increment if
the subject's STAI score is reduced by 1 or more points.
[0107] The patient anxiety may also be measured by one of the
following anxiety rating scales: State-Trait Anxiety Inventory
(STAI), the Fear Survey Schedule, Beck Anxiety Inventory (BAI),
Brief Fear of Negative Evaluation Scale--BFNE, Clinician
Administered PTSD Scale (CAPS), Daily Assessment of
Symptoms--Anxiety, Generalized Anxiety Disorder 7 (GAD-7), Hamilton
Anxiety Scale (HAM-A), Hospital Anxiety and Depression Scale
(HADS-A), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety
Severity and Impairment Scale (OASIS), Panic and Agoraphobia Scale
(PAS), Panic Disorder Severity Scale (PDSS), PTSD Symptom
Scale--Self-Report Version, Social Phobia Inventory (SPIN), Trauma
Screening Questionnaire, Yale-Brown Obsessive Compulsive Scale
(Y-BOCS), and the Zung Self-Rating Anxiety Scale.
[0108] Depression Rating Scales
[0109] The depression rating scales listed herein are known to
those skilled in the art. For example, Hamilton Depression Rating
Scale (HAM-D) may be used to determine a patient's level of
depression. The HAM-D lists 21 items, but scoring is based on the
first 17 in which 0-6 is considered normal, 7-17 is considered mild
depression, 18-24 is considered moderate depression, and 25 and
greater is considered severe depression (Cusin 2009). Other
depression rating scales are described in Bech 2001, Bech 2006,
Strik 2001, and Cusin 2009.
[0110] As used here, "reducing depression by at least one
increment" means that the patient's depression as measured by at
least one of the specific depression rating scales is lessened. For
example, in the HAM-D scale discussed above, the subject's
depression is reduced by at least one increment if the subject's
HAM-D score is reduced by 1 or more points.
[0111] The patient's depression may also be measured by one of the
following depression rating scales: Hamilton Rating Scale for
Depression (HAM-D), Beck Depression Inventory (BDI), Beck
Hopelessness Scale, Centre for Epidemiological Studies-Depression
Scale (CES-D), Patient Health Questionnaire, Center for
Epidemiological Studies Depression Scale for Children (CES-DC),
Clinically Useful Depression Outcome Scale, Diagnostic Inventory
for Depression, Edinburgh Postnatal Depression Scale (EPDS),
Inventory of Depressive Symptomatology, Geriatric Depression Scale
(GDS), Hospital Anxiety and Depression Scale, Kutcher Adolescent
Depression Scale (KADS), Major Depression Inventory (MDI),
Montgomery-Asberg Depression Rating Scale (MADRS), Mood and
Feelings Questionnaire (MFQ), Zung Self-Rating Depression Scale, or
Cornell Scale for Depression in Dementia (CSDD).
[0112] PBA-S-Test
[0113] In another embodiment, PBA-S is a measure of depression and
anxiety.
[0114] The Problem Behaviors Assessment for Huntington
Disease-Short Form (PBA-s) is an interview designed specifically
for rating the severity and frequency of behavioral abnormalities
in HD. PBA-S includes behavioral assessments of depressed mood,
anxiety, apathy and irritability. This scale is widely used in HD
clinical trial and recommended as a measure of screening behavioral
symptoms, including depression and anxiety (Mestre et al, MDS
2016).
[0115] Because of the prominence of psychiatric symptoms in HD, it
was recommended that the PBA-s form be used in all HD studies with
any need for behavioral assessment as a comprehensive screen for
the most common psychiatric symptoms in HD (Craufurd 2001, Kingma
2008). The PBA-s also includes questions concerning suicidal
behavior, a particular concern in HD. The PBA-s is based on the
same set of core behavioral symptoms as the UHDRS Behavioral
questions, which were used previously as the global psychiatric
measure in most HD studies. The PBA-s has more detailed questions
and more specific guidance on administration and scoring
[0116] The PBA-s is a brief semi-structured interview covering the
most common behavioral and psychiatric manifestations of HD. The
interview is not restricted to a single construct, but rather
covers several broad symptom domains relevant to HD, comprising 11
items: low mood, suicidal ideation, anxiety, irritability,
anger/aggressive behavior, loss of motivation, perseverative
thinking or behavior, obsessive-compulsive behaviors, paranoid
thinking, hallucinations, behavior suggestive of disorientation.
Each symptom is rated for severity on a 5-point scale according to
detailed scoring criteria which roughly correspond to the
following: 0="not at all"; 1=trivial; 2=mild; 3=moderate
(disrupting everyday activities) and 4=severe or intolerable. Each
symptom is also scored for frequency on a 5-point scale as follows:
0=symptom absent; 1=less than once weekly; 2=at least once a week;
3=most days (up to and including some part of everyday); and 4=all
day, every day. Severity and frequency scores are multiplied to
produce an overall `PBA score` for each symptom.
[0117] The reliably of the PBA-S score to assess behavioral
problems in HD patients was studied in 732 patients from the
TRACK-HD observational study. This study provides strong evidence
that the PBA-s is a reliable instrument for assessing depressed
mood, anxiety and apathy behavioral problems in HD (Callaghan et
al, J Neuropsychiatry Clin Neurosci 2015)
[0118] Reliability of the PBA-s to assess behavioral problems in HD
was also investigated in 152 HD patients vs 56 healthy controls. HD
patients portrayed more apathy, depression and irritability than
controls. The study also concluded that the PBA-s is a reliable and
sensitive instrument for the evaluation of apathy, depression and
irritability (Kingma et al, Gen Hosp Psychiatry. 2008).
[0119] To aid in efficient development of new HD research studies,
the National Institute of Neurological Disorders and Stroke (NINDS)
published recommendations for measurement selection in HD. NINDS
recommended the use of the PBA-s scale for behavioral assessments
instead of the UHDRS Behavioral Exam because the PBA-s showed
support for reliability and validity in HD as well as a sensitive
measure for responsiveness to change in HD (Carlozzi et al, J
Huntingtons Dis. 2014)
[0120] Forced Swim Test (FST)-Test
[0121] Forced swim test (FST), is one of the most commonly used
assays for the study of depressive-like behavior in rodents. When
placing a rodent (mouse or rat) in a container filled with water,
it will first make efforts to escape but eventually will exhibit
immobility that is considered to reflect a measure of behavioral
despair. This test has been extensively used because it involves
the exposure of the animals to stress, which was shown to have a
role in the tendency for major depression. Additionally, the FST
has been shown to share some of the factors that are influenced or
altered by depression in humans, including changes in food
consumption, sleep abnormalities and drug-withdrawal-induced
anhedonia. Moreover, its sensitivity to a broad range of
antidepressant drugs that makes it a suitable screening test is one
of the most important features leading to its high predictive
validity.
[0122] Marble Burying--Test
[0123] Marble burying test is an animal model used in scientific
research to depict anxiety or obsessive-compulsive disorder (OCD)
behavior. It is based on the observation that rats and mice will
bury either harmful or harmless objects in their bedding. When
rodents are put in a cage with marbles they will bury the marbles.
This behavior is seen as anxiety related or OCD behavior. When the
rodents are injected with drugs used to treat anxiety or OCD, the
amount of marbles buried decreases. The test is also sensitive to
antidepressant agents.
[0124] Ultrasonic Vocalizations (UST)--Test
[0125] In neonatal mice ultrasonic vocalizations test have been
studied both as an early communicative behavior of the pup-mother
dyad and as a sign of an aversive affective state. Adult mice of
both sexes produce complex ultrasonic vocalization patterns in
different experimental/social contexts. All these vocalizations are
becoming an increasingly valuable assay for behavioral phenotyping
throughout the mouse life-span and alterations of the ultrasound
patterns have been reported in several mouse models of
neurodevelopmental disorders. This test is a reliable method for
detecting anxiolytic properties of test compounds.
EXPERIMENTAL DETAILS
Example 1: Evaluation of Pridopidine in Transgenic YAC128 Mouse
Model of Huntington Disease
[0126] Pridopidine is currently in clinical development for
Huntington disease (HD) and ALS.
[0127] This study investigated the efficacy and mechanism of action
of pridopidine using the transgenic YAC128 mouse model of HD
(Garcia-Miralles 2016). Pridopidine was administered to animals
starting at early (1.5 months of age) or late stages of disease (8
months of age). In the early treatment cohort, animals were divided
into two groups receiving vehicle or 30 mg/kg of pridopidine for a
period of 10.5 months. In the late cohort, animals were divided
into two groups receiving either 0 mg/kg or an escalating dose of
pridopidine (10 mg/kg in week 1, 20 mg/kg in week 2, and 30 mg/kg
in weeks 3-8). Pridopidine treated animals were evaluated using a
battery of behavioral tests. Analysis reveals that chronic
treatment with pridopidine improves anxiety-like and
depressive-like phenotypes in the YAC128 HD mice.
[0128] Materials and Methods:
[0129] Animals. Male and female YAC128 HD mice (line 53) expressing
a full-length human HTT (huntingtin) transgene with 128 CAG
repeats, maintained on the FVB/N strain were used. Mice were bred
at the Biological Resource Centre (Agency for Science, Technology
and Research, ASTAR), and group-housed with littermates of mixed
genotype. Animals were maintained under a 12-h light cycle (lights
on at 09:00) in a clean facility, and given free access to food and
water. Experiments were performed with the approval of the
Institutional Animal Care and Use Committee at the Biomedical
Sciences Institute (ASTAR) and in accordance with their approved
guidelines.
[0130] Administration of pridopidine. Pridopidine was dissolved in
sterile water. Pridopidine and vehicle were administered daily by
oral gavage for five days/week for 10.5 months for the early
treatment cohort and 8 weeks for the late treatment cohort. Mice
received vehicle (sterile water) or 30 mg/kg of pridopidine at a
volume of 4 mL/kg. Animals were weighed every two weeks to ensure
the correct dose was maintained.
[0131] Study Design.
[0132] Late treatment cohort: Pridopidine was administered to
animals in advanced stages of disease (8 months of age). At this
age, mice present striatal atrophy and profound behavioural
deficits. Animals were divided into two groups receiving either 0
mg/kg or an escalating dose of pridopidine (10 mg/kg in week 1, 20
mg/kg in week 2, and 30 mg/kg in weeks 3-8). A forced swim test was
executed at 9.5 months of age. Mice were sacrificed following
completion of behavioural testing at 10 months of age.
[0133] Early treatment cohorts: Pridopidine was administered to
animals (two cohorts) in the early stages of disease (1.5 months of
age). Mice were divided into three groups. A group of YAC128 HD
mice received pridopidine at a dose of 30 mg/kg, whereas the
remaining groups, WT mice and YAC128 HD mice, received an
equivalent volume of vehicle. One cohort was behaviourally tested
every two months commencing at 2 months of age. Mice were tested
for psychiatric function (open field, elevated plus maze, and
forced swim test). Tests were conducted at a set time during the
day, prior to drug administration.
[0134] Pridopidine was administered to animals starting at early
(1.5 months of age) or late stages of disease (8 months of age) 5
days a week by oral gavage. Table 1 shows the treatment protocol
for early stage disease cohort (1.5 mo old YAC128 HD mice). Table 1
shows the treatment protocol for late stage disease cohorts (8 mo
old YAC128 HD mice).
TABLE-US-00001 TABLE 1 Early stage pridopidine treatment
Pridopidine early treatment groups Genotype Pridopidine dose
(mg/kg) Sex Number Total N/treatment WT 0 F 10 20 M 10 YAC128 0 F
10 20 M 10 YAC128 30 F 10 20 M 10
TABLE-US-00002 TABLE 2 Late stage pridopidine treatment Pridopidine
late treatment groups Genotype Pridopidine dose (mg/kg) Sex Number
Total N/treatment WT 0 0 0 F 3 12 M 9 YAC128 0 0 0 F 3 9 M 9 YAC128
10 20 30 F 3 10 M 7
[0135] Tests of Affective Function
[0136] Anxiety-like behavioral tests. The open-field (OF) and
elevated plus maze (EPM) tests are used to assess anxiety-like
behavioral in rodents. The time spent in the center of the arena in
the OF and the time spent in the open arms of the maze in the EPM
are considered measures of anxiety-like behavior.
[0137] Depressive-like behavioral tests. The Porsolt forced-swim
test (FST) is used to assess depressive-like behavior in rodents.
The time spent immobile is considered a measure of depressive-like
behavior. Immobility scores for each mouse were determined by
manual scoring.
[0138] Results
[0139] A 30 mg/kg dose of pridopidine showed beneficial effects on
anxiety- and depressive-like behaviors in HD YAC128 mice. The
improvements were seen throughout the disease course, with reduced
anxiety-like phenotypes at 6 and 8 months of age, and amelioration
of depressive-like behaviour at 12 months of age.
[0140] The improvements in behavioural outcomes are not likely to
represent acute effects given pridopidine's short half-life and the
fact that on test days, pridopidine was administered after the
behavioural assays were completed. Furthermore, the effects appear
to be HD-specific as no effects were seen in treated WT mice (data
not shown). In contrast, when pridopidine was administered to mice
at a later time point when the disease was clearly manifest, the
functional benefits were limited, although improvements in
depressive-like behaviour were noted.
[0141] These findings show that early administration of pridopidine
exhibits anxiolytic and antidepressant properties in YAC128 HD
mice, and therefore may be used for the treatment psychiatric
symptoms. This data also shows that late administration of
pridopidine in manifest YAC128 HD mice is efficacious to treat
depressive-like phenotypes.
Example 2: Anti-Depressive Effect in the Rat Forced Swim Test Using
Pridopidine (FIGS. 5A and 5B)
[0142] Sprague-Dawley male rats, 6 weeks old were used. Rats were
pre-tested on day 1 to ensure stable and high duration of
immobility during the 5-min test session. Rats were then treated
daily with pridopidine at 3 or 15 mg/kg by oral gavage for 7 days.
On day 8, rats were administered the FST 30 minutes after
pridopidine administration. Pridopidine decreased immobility time
in rats by 38% and 58% in the 3 and 15 mg/kg groups, respectively
(FIG. 5B). This indicates an anti-depressive effect of pridopidine
in rats. This example demonstrates that pridopidine is a promising
therapeutic target for depressive behavior.
Example 3: Pridopidine Shows an Anxiolytic Effect in the Marble
Burying Test in Mice (NS) (FIG. 6)
[0143] Inhibition of object-burying in rodents is proposed as an
animal model of anxiety because anxiolytic drugs reduce duration
and extent of burying (Broekkamp et al, 1986; Treit, 1985; Treit et
al, 1981).
[0144] Materials and Methods
[0145] Animals
[0146] Male NMRI mice (20-36 g body weight) were housed in groups
of five in a temperature (20.+-.2.degree. C.) and humidity (50-60%)
controlled colony room under a non-reversed 12 (6-18 on)/12 h
light-dark cycle with food and water ad libitum except during the
actual experiments. 8 mice were used for each drug dose and 16 mice
for the vehicle-treated control group. Animals were assigned
according to the experimental plan to one of the 4 test boxes run
simultaneously.
[0147] Procedure
[0148] 30 min after drug application (pridopidine), mice were
individually placed for 30 min in an open box (L 44 cm, W 43 cm, H
52 cm) filled with 5 cm of sawdust bedding material. 25 clean glass
marbles (2 cm in diameter) were evenly spaced on the sawdust. The
number of marbles covered by sawdust were counted. The experimenter
also observed the animals for obvious inhibition of general
activity (locomotor activity). Experiments were done between 8:30
and 12.00 a.m.
[0149] Drugs
[0150] Pridopidine was suspended in 5% gum Arabic for p.o.
application (application volume 1 ml/kg bodyweight).
[0151] Results
[0152] Pridopidine treatment resulted in inhibition of
marble-burying at all doses tested, in a dose-dependent manner
(FIG. 6). 1 mg/kg demonstrated 8% inhibition; 3 mg/kg demonstrated
49% inhibition; 10 mg/kg demonstrated 62% inhibition; and 30 mg/kg
demonstrated 73% inhibition.
[0153] Marble burying also represent an animal model for
Obsessive-compulsive disorder.
Example 4: Pridopidine Shows Anxiolytic Effects in the Rat
Ultrasonic Vocalization (USV) Test (FIG. 7)
[0154] The ultrasonic vocalization (USV) test in young adult rats
is one of the most robust animal models of anxiety amongst the
various animal models used to detect anxiolytic-like effects in
animals.
[0155] Materials and Methods
[0156] Animals
[0157] Male Sprague-Dawley rats (270-400 g bodyweight) were housed
in groups of two in a temperature (20.+-.2.degree. C.) and humidity
(50-60%) controlled colony room under a non-reversed 12 (6-18
on)/12 h light-dark cycle with food and water ad libitum except
during the actual experiments. 4 rats were used for each drug dose
and the vehicle-treated control group.
[0158] Procedure
[0159] As described elsewhere (Bartoszyk G D (1998) Life Sci 22:
649-663; and Bartoszyk GD, (1997) Eur J Pharmacol 322: 147-153) USV
was measured in a sound-attenuated test chamber (W 24 cm, L 22 cm,
H 22 cm) with a grid floor for delivery of foot-shock (scrambled
shock of 0.2 mA for 0.5 s). USV was recorded by a microphone and
processed by an interface to select USV signals and to digitize the
resulting signals for automatic processing. In the priming phase,
each rat was placed in the test chamber. After a 2 min time period,
a series of at most ten shocks (trials), 1.8 mA for 0.3 s,
separated by 20 s shock-free intervals, was delivered via the grid
floor of the test chamber. In the shock-free intervals the
occurrence of ultrasonic vocalization (22.+-.5 kHz) was
automatically recorded, and the duration of ultrasonic vocalization
was calculated immediately. The priming session was terminated
either when the rat constantly vocalized at least for 10 s on three
consecutive trials or after the tenth trial. Rats not responding
with USV on three consecutive trials were excluded from the test.
In the actual test performed on the next day, each rat received 5
initial shocks (1.8 mA for 0.3 s, separated by 20 s shock-free
intervals) in the test chamber, and the duration of USV (22+4 kHz)
was recorded during the following 3 min period. Animals were
repeatedly tested 30 and 120 min after pridopidine
administration.
[0160] Drugs
[0161] Pridopidine was suspended in gum Arabic for p.o. application
(application volume 10 ml/kg bodyweight).
[0162] Results
[0163] Following oral administration, pridopidine 30 mg/kg
significantly inhibited USV in young adult rats 30 min and 120 min
after administration (FIG. 7).
Example 5: Pridopidine is Effective in Non-HD Rodent Models of
Anxiety
[0164] Pridopidine is administered periodically (e.g., daily or
twice daily) to rodents exhibiting symptoms of anxiety. Examples of
rodent models include the HAB rats, selected on the basis of their
behavior in the elevated plus maze (EPM); the Syracuse High and Low
Avoidance rats; the Maudsley reactive/nonreactive strains; the
Tsukuba High and Low Emotional rats, and the Floripa H and L lines
a rat model of anxiety and depression. The Roman Low-Avoidance
(RLA) rats, selected on the basis of poor acquisition of a two-way
avoidance response in the shuttle box, are considered as a model of
high trait anxiety-emotionality. Selective breeding of rats and
mice improves the probability of discovering anxiety-related
neurobiological correlates, including genetic determinants, and
allows the study of gene-environment interactions. (Steimer
2011).
[0165] Administering pridopidine is effective in treating anxiety.
Administering pridopidine is effective in reducing symptoms of
anxiety.
Example 6: Pridopidine Improves Problem Behaviors Assessment-Short
(PBA-S) in Pride-HD (FIGS. 8 and 9)
[0166] The Problem Behaviors Assessment-Short (PBA-s) scale, is a
measure of psychiatric symptoms including anxiety, depression and
apathy. The PBA-s is an interview designed specifically for rating
the severity and frequency of behavioral abnormalities in HD. PBA-S
includes behavioral assessments of depressed mood, anxiety, apathy
and irritability. This scale is widely used in HD clinical trials
and recommended as a measure of screening behavioral symptoms,
including depression and anxiety. The effect of pridopidine on
PBA-S in patients with HD in the Pride-HD clinical trial was
assessed. After 52 weeks, a trend towards improvement of -2.13
units was demonstrated (p=0.0603) (FIG. 8). The lack of initiative
subscale of the PBA-S is a measure of apathy in HD patients. Apathy
is a symptom common to HD and depression. Pridopidine treatment
demonstrates a trend towards improvement of -1.27 units was
observed in the PBA-S lack of initiative measure (p=0.0704) (FIG.
9).
Example 7: Assessment of Efficacy of Pridopidine In Treating
Patients Suffering from Anxiety or Depression
[0167] Pridopidine is administered periodically (e.g., daily or
twice daily) to a patient diagnosed with anxiety or depression. The
patient is exhibiting symptoms of anxiety or depression. The
pridopidine is administered intravenously or orally. Administering
pridopidine is effective in treating the patient. Administering
pridopidine is also effective in reducing one or more of the
symptoms of anxiety or of depression. Administering pridopidine is
effective in facilitating rehabilitation of the patient.
[0168] Administering pridopidine is effective in facilitating
rehabilitation of affective functions of the patient. Administering
pridopidine is also effective in facilitating rehabilitation of
behavioral function of the patient. Administering pridopidine is
also effective in facilitating rehabilitation of emotional function
of the patient. Administering pridopidine is also effective in
facilitating rehabilitation of psychiatric function of the patient.
Administering pridopidine is also effective in facilitating
rehabilitation of sensory function of the patient.
Example 8: A Phase III, A Randomized, Double-Blind, Placebo
Controlled, Parallel Arm, Multicenter Study Evaluating the Efficacy
and Safety of Pridopidine in Patients with Early Stage of
Huntington Disease
[0169] Objective
[0170] The proposed Phase 3 study is a 65 to 78-week, multicenter,
randomized, double-blind, placebo controlled, parallel group study
to evaluate the efficacy and safety of pridopidine administered at
a dose of 45 mg bid in adult patients with early stage HD (TFC
7-13). Evaluation will be of total functional capacity, motor and
behavioural features of HD in early-stage participants.
[0171] Methods
[0172] The study consists of a screening period; a 2-week titration
period; a 63-week, double-blind, full-dose treatment period; and a
variable double-blind, full-dose treatment period up to 78 weeks,
with a 2-week follow-up period.
[0173] Participants will be those with stage 1-2 HD, which is
defined as a UHDRS-TFC score of .gtoreq.7, at screening. Further,
participants must have an UHDRS-Independence scale (IS) score of
.ltoreq.90% at screening and a UHDRS-TMS .gtoreq.20.
[0174] During the screening period, patients provide informed
consent and subsequently undergo assessments to determine
eligibility for participation in the study. The stage of HD is
established by the UHDRS TFC scale. The TMS and UHDRS-IS are
assessed.
[0175] Eligible patients are invited to return for a baseline visit
and baseline assessments. Those patients who remain eligible for
study participation will be randomly assigned (1:1 ratio) to 1 of
the 2 treatment groups: 45 mg bid pridopidine or placebo bid. For
patients assigned to receive pridopidine, the dose is titrated
during the first 2 weeks from 45 mg qd to the final dose of 45 mg
bid pridopidine.
[0176] Overall Design of the Study:
[0177] The screening period will be followed by a 65 to 78 weeks
double-blind treatment period, composed of a 2-week titration
period, a 63 week double-blind full-dose maintenance treatment
period followed by a variable double blind treatment period of up
to 13 weeks (total of up to 78 weeks; Main study).
[0178] On Day 1 (Baseline visit), eligible participants will be
randomized in a 1:1 ratio to active (pridopidine 45 mg bid) or
control (placebo) arm.
[0179] Starting on Day 1, during the titration period, all
participants will self-administer 1 capsule of study drug per os
(PO-taken orally), once daily (qd), in the morning for 2 weeks.
Thereafter, study drug will be taken PO bid in the morning and in
the afternoon for 63 weeks (full-dose maintenance double-blind
treatment period). Participants who complete the maintenance period
(63 weeks) will continue into a variable double-blind period of up
to 13 weeks or until the last participant randomized completes 65
weeks of treatment (2 weeks titration+63 weeks full dose),
whichever comes first.
[0180] The Open Label Extension (OLE) will consist of a 2-week up
titration period and a maintenance period. During the up-titration
period, participants will self-administer 1 capsule of pridopidine
45 mg PO, qd, in the morning, for 2 weeks. Thereafter, pridopidine
will be taken PO, bid in the morning and in the afternoon. Table 3
below presents the participants and study groups, FIG. 10 provides
a Study Schema for the Main Study, and FIG. 11 provides the Study
Schema for the Open-Label Extension (OLE).
TABLE-US-00003 TABLE 3 Treatment Groups - Main Study Dose and dose
regimen Titration Period Maintenance Period Number of Treatment (2
weeks) (65 to 78 weeks) participants Active - 45 mg capsule 45 mg
capsule PO, bid 240 pridopidine PO, qd (total daily dose of 90 mg)
Control - Capsule, PO, qd Capsule, PO, bid 240 matching placebo
[0181] Pridopidine Dose Formulation, Route of Administration,
Strength, and Levels
[0182] 45 mg Pridopidine is provided in the form of a hard gelatin
capsule for oral administration. The titration period includes
administration of 45 mg capsule qd (on-prescription; morning dose)
for 2 weeks, followed by the main full-dose treatment period
wherein participants will take 45 mg capsule bid (1 capsule in the
morning and 1 capsule in the afternoon, 7 to 10 hours after morning
dose) for a total daily dose of 90 mg.
[0183] Primary Endpoint
[0184] The primary efficacy endpoint to be evaluated is the change
from baseline in UHDRS-TFC to week 65 in patients treated with
pridopidine 45 mg bid compared to patients receiving placebo.
[0185] Secondary and Exploratory Endpoints
[0186] Secondary endpoints will include: (a) Proportion of
participants with no worsening (change .gtoreq.0 point) from
baseline to Week 65 in UHDRS-TFC (b) Change from baseline to Week
65 in the UHDRS-Total Motor Score (TMS) (c) Change from baseline to
Week 65 in Quantitative motor (Q-Motor) finger tapping
(Digitomotography) (d) Change from baseline to Week 65 in Composite
UDHRS (cUHDRS) total score (e) Change from baseline to Week 52 in
UHDRS-TFC score (f) Change from baseline to Week 52 in UHDRS-TMS
score (g) Proportion of participants with no worsening from
baseline in Clinical Global Impression of Change (CGI-C) at Week
65
[0187] (h) Change from baseline to Week 78 in UHDRS-TFC score (i)
Change from baseline to week 26, 52, 65 and 78 in PBA-s (j) Change
from baseline to week 26, 52, 65 and 78 in PBA-s lack of
initiative
[0188] The human patient's behavior and/or psychiatric state may be
measured by the Problem Behaviors Assessment (PBA) total score. The
human patient's behavior and/or psychiatric state may also be
measured by the Problem Behaviors Assessment-short form (PBA-s).
The human patient's behavior and/or psychiatric state may also be
measured by the Problem Behaviors Assessment for depressed mood.
The human patient's behavior and/or psychiatric state may also be
measured by the Problem Behaviors Assessment for irritability. The
human patient's behavior and/or psychiatric state may also be
measured by the Problem Behaviors Assessment for lack of initiative
or apathy. The human patient's behavior and/or psychiatric state
may also be measured by the Problem Behaviors Assessment short form
apathy sub-item. The human patient's behavior and/or psychiatric
state may also be measured by the Apathy Evaluation Scale (AES).
The human patient's behavior and/or psychiatric state may be
measured by the Problem Behaviors Assessment for
obsessive-compulsiveness. The human patient's behavior and/or
psychiatric state may also be measured by the Problem Behaviors
Assessment for disoriented behavior. In some embodiments, the human
patient's behavior and/or psychiatric state is measured by the
Problem Behaviors Assessment short form apathy sub-item or the
Problem Behaviors Assessment-short form (PBA-s).
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